Abstract:

The invention relates to chemical compounds, or pharmaceutically
acceptable salts thereof of the formula (Q) or (I), which penetrate the
blood-brain barrier, inhibit the formation and accumulation of
beta-amyloid, and are useful in the treatment of neurodegenerative
diseases, particularly Alzheimer's disease. Further, the compounds of the
present invention inhibit certain kinases, thereby being useful for the
treatment of cancers of the central nervous system.
##STR00001##

Claims:

1. A compound of formula (Q): ##STR00020## in free or salt form,
wherein:A1 is --C(R7)-- or --N--;A2 and A3 are
independently --C-- or --N--, wherein at least one of A2 and A3
must be N; and wherein when A2 is --C--, it optionally is
substituted with R8;W is --O-- or --N(C0-6alkyl)-;Y is
--NHCO--, --CONH--, --NHSO2--, --NHCONH--, or --NHCH2--;D is a
5 or 6 membered aryl, hetaryl or hetcyclic ring having at least one N, S,
or O ring atom, or a C ring atom forming an oxo (C═O) moiety;R1
is C1-6alkyl, aryl, or hetaryl; optionally substituted except at the
ortho position of the aryl or hetaryl with 1-6 halo, C1-6alkoxy,
C1-6allyl, or trifluoromethyl substituents; wherein the ortho aryl
or hetaryl position is unsubstituted;R2 is C0-6alkyl,
C3-7cycloalkyl, aryl, hetaryl, aryl(C1-4alkyl)-,
hetcyclyl(C0-4alkyl)-, or
--C0-6alkyl-N(C0-6alkyl)(C0-6alkyl), optionally
substituted with C1-6 alkyl; andR3, R4, R5, R6,
R7 and R8 are independently selected from hydrogen, halo,
C1-4alkyl, C1-4alkoxyl, and haloC1-4alkyl.

2. The compound according to claim 1 wherein the compound of formula (Q)
is: ##STR00021## in free or salt form.

3. The compound according to claim 1 wherein the compound of formula (Q)
is ##STR00022## in free or salt form.

4. The compound according to claim 1 wherein the compound of formula (Q)
is ##STR00023## in free or salt form.

5. The compound according to claim 1 wherein the compound of formula (Q)
is ##STR00024## in free or salt form.

6. The compound according to claim 1 wherein the compound of formula (Q)
is: ##STR00025## in free or salt form.

7. The compound according to claim 1 wherein the compound of formula (Q)
is: ##STR00026## in free or salt form.

8. The compound according to claim 1 wherein the compound of formula (Q)
is: ##STR00027## in free or salt form.

9. A compound of formula (I): ##STR00028## in free or salt form,
wherein:A1 is CH or N;A2 and A3 are independently CH or N,
wherein at least one of A2 and A3 must be N; and wherein when
A2 is C, it optionally is substituted with halo, methyl, methoxy, or
trifluoromethyl;W is --O-- or --N(C0-6alkyl)-;Y is --NHCO--,
--CONH--, --NHSO2--, --NHCONH--, or --NHCH2--;D is a 5 or 6
membered aryl, hetaryl or hetcyclic ring having at least one N, S, or O
ring atom, or a C ring atom forming an oxo (C═O) moiety;R1 is
C1-6alkyl, aryl, or hetaryl; optionally substituted except at the
ortho position of the aryl or hetaryl with 1-6 halo, C1-6alkoxy,
C1-6alkyl, or trifluoromethyl substituents; wherein the ortho aryl
or hetaryl position is unsubstituted; andR2 is C0-6 alkyl,
C3-7cycloalkyl, aryl, hetaryl, aryl(C1-4alkyl)-,
hetcyclyl(C0-4alkyl)-, or
--C0-6alkyl-N(C0-6alkyl)(C0-6alkyl), optionally
substituted with C1-6alkyl.

10. A pharmaceutical composition which comprises a compound of claim 1, in
free or pharmaceutically acceptable salt form, in association with a
pharmaceutically-acceptable diluent or carrier.

11. A method of treatment of a disease or disorder characterized as a
neurodegenerative disease comprising administering an effective amount of
the compound according to claim 1, in free or pharmaceutically acceptable
salt form, to a patient in need thereof.

13. The method according to claim 11, wherein said disease or disorder is
Alzheimer's disease.

14. A method of treatment of a disease or disorder characterized as
hyperproliferative comprising administering the compound according to
claim 1, in free or pharmaceutically acceptable salt form, to a patient
in need thereof.

15. A method of treatment, control and management of diseases
characterized by accumulation of abnormal protein aggregates comprising
administering an effective amount of the compound according to claim 1,
in free or pharmaceutically acceptable salt form, to a patient in need
thereof.

16. The method of claim 15, wherein said disease is characterized by
accumulation of abnormal protein aggregates in the brain.

17. (canceled)

18. A method of treatment, control and management of vascular,
neurological, or neurodegenerative disorders related to the abnormal
expression or accumulation of tau or amyloid proteins, comprising
administering an effective amount of the compound according to claim 1,
in free or pharmaceutically acceptable salt form, to a patient in need
thereof.

19. The method of claim 15, wherein the disease or disorder characterized
by the accumulation of abnormal protein aggregates is selected from the
group consisting of: amyloid plaques, neurofibrillary tangles, or
precipitates of tau or amyloid proteins.

20. (canceled)

21. A method of treatment of disease or disorders characterized as cancers
of the brain or central nervous system, comprising administering an
effective amount of the compound according to claim 1, in a free or
pharmaceutically acceptable salt form, to a patient in need thereof.

28. A method of treatment of a disease or disorder characterized by
dysfunctional kinase expression or kinase activity comprising
administering an effective amount of the compound according to claim 1,
in free or pharmaceutically acceptable salt form, to a patient in need
thereof.

Description:

[0001]This application claims priority from U.S. Provisional Application
No. 60/933,782, filed Jun. 7, 2007, the contents of which are hereby
incorporated by reference in their entirety.

FIELD OF THE INVENTION

[0002]The present invention relates to novel heterocycles, their
pharmaceutical compositions and methods of use. In addition, the present
invention relates to therapeutic methods that penetrate the blood-brain
barrier and inhibit the formation and accumulation of beta-amyloid.
Accordingly, the compounds and compositions of the present invention are
useful in the treatment of neurodegenerative diseases, particularly
Alzheimer's disease. Further, the compounds of the present invention
inhibit certain kinases, thereby being useful for the treatment of
cancers of the central nervous system.

BACKGROUND OF THE INVENTION

[0003]Without being bound to theory, it is believed that the pathology of
Alzheimer's disease ("AD") involves amyloid-β ("Aβ") peptides,
which are metabolites of β-amyloid precursor protein (Alzheimer's
disease-associated precursor protein or "APP"), and are believed to be
major pathological determinants of AD. These peptides consist mainly of
40 to 42 amino acids, Aβ1-40 ("Aβ40") and Aβ1-42
("Aβ42"), respectively. Aβ40 and Aβ42 are generated by two
enzymatic cleavages occurring close to the C-terminus of APP. The enzymes
responsible for the cleavage, β-secretase and γ-secretase,
generate the N- and C-termini of Aβ, respectively. The amino
terminus of Aβ is formed by β-secretase cleavage between
methionine residue 596 and aspartate residue 597 of APP (numbering based
o APP 695 isoform). γ-secretase cleaves at varying positions 38-,
40- or 43-residues C-terminal of this β-secretase cleavage product
to release the Aβ peptides. A third enzyme, α-secretase,
cleaves the precursor protein between the Aβ- and γ-cleavage
sites, thus precluding Aβ production and releasing an approximately
3 kDa peptide known as P3, which is non-pathological. Both β- and
α-secretase cleavage also result in soluble, secreted-terminal
fragments of APP, known as sAPPβ and sAPPα, respectively. The
sAPPα fragment has been suggested to be neuroprotective. These
secretases may also be involved in the processing of other important
proteins. For example, γ-secretase also cleaves Notch-1 protein.

[0004]A drug which selectively inhibits Aβ formation and/or
accumulation is thus of potential interest for the treatment, management
and prevention of Alzheimer's disease. To maximize utility, however, it
is also desirable that it can be readily delivered to relevant site of
action in the brain. Brain is protected from chemical insult by a
selective barrier, referred to as the blood-brain barrier ("BBB"), that
many drug-like compounds are unable to penetrate.

[0005]International Patent Publication No. WO 03/057165 discloses that
certain previously known inhibitors of tyrosine kinases are useful to
inhibit the production of and accumulation of Aβ. Such compounds
included those described in U.S. Pat. No. 5,521,184, which includes
imatinib. Netzer et al., Proc Natl Acad Sci., 100(21):12444-9 (2003)
showed that imatinib inhibits production of Aβ without affecting
γ-secretase cleavage of Notch-1 and without unacceptable toxicity
to the neurons. A major disadvantage with using imatinib for the
treatment or prevention of Alzheimer's disease, however, is that
penetration of this compound across the BBB is poor because imatinib is
actively pumped out of the brain by a P-glycoprotein system, thereby
preventing high concentrations of the compound from accumulating in the
brain. Accordingly, imatinib is generally not used for the treatment of
cancers of the central nervous system.

in free or salt form, which penetrate the blood-brain barrier, inhibit the
formation and accumulation of beta-amyloid, and are useful in the
treatment of neurodegenerative diseases, particularly Alzheimer's
disease. Further, the compounds of the present invention inhibit certain
kinases, thereby being useful for the treatment of cancers of the central
nervous system.

[0008]The present invention is also directed to compounds of formula (I):

##STR00003##

which penetrate the blood-brain barrier, inhibit the formation and
accumulation of beta-amyloid, and are useful in the treatment of
neurodegenerative diseases, particularly Alzheimer's disease. Further,
the compounds of the present invention inhibit certain kinases, thereby
being useful for the treatment of cancers of the central nervous system.

DETAILED DESCRIPTION OF THE INVENTION

[0009]In one aspect, the compounds of the present invention are presented
by

##STR00004##

in free or salt form, wherein:

[0010]A1 is --C(R7)-- or --N--;

[0011]A2 and A3 are independently --C-- or --N--, wherein at
least one of A2 and A3 must be N; and wherein when A2 is
--C--, it optionally is substituted with R8;

[0012]W is --O-- or --N(C0-6alkyl)-;

[0013]Y is --NHCO--, --CONH--, --NHSO2--, --NHCONH--, or
--NHCH2--;

[0014]D is a 5 or 6 membered aryl, hetaryl or hetcyclic ring having at
least one N, S, or O ring atom, or a C ring atom forming an oxo (C═O)
moiety;

[0015]R1 is C1-6alkyl, aryl, or hetaryl; optionally substituted
except at the ortho position of the aryl or hetaryl with 1-6 halo,
C1-6alkoxy, C1-6alkyl, or trifluoromethyl substituents; wherein
the ortho aryl or hetaryl position is unsubstituted;

[0018]In another aspect, the compounds of the present invention are
represented by formula (I):

##STR00005##

in free or salt form, wherein:

[0019]A1 is CH or N;

[0020]A2 and A3 are independently CH or N, wherein at least one
of A2 and A3 must be N; and wherein when A2 is C, it
optionally is substituted with halo, methyl, methoxy, or trifluoromethyl;

[0021]W is --O-- or --N(C0-6alkyl)-;

[0022]Y is --NHCO--, --CONH--, --NHSO2--, --NHCONH--, or
--NHCH2--;

[0023]D is a 5 or 6 membered aryl, hetaryl or hetcyclic ring having at
least one N, S, or O ring atom, or a C ring atom forming an oxo (C═O)
moiety;

[0024]R1 is C1-6alkyl, aryl, or hetaryl; optionally substituted
except at the ortho position of the aryl or hetaryl with 1-6 halo,
C1-6alkoxy, C1-6alkyl, or trifluoromethyl substituents; wherein
the ortho aryl or hetaryl position is unsubstituted; and

[0026]In one aspect, the compounds of the present invention are
represented by Formula I in free or salt form, wherein W is --O-- and the
other variables are as defined above for Formula I.

[0027]In an embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--O--; Y is --NHCO--; and the other variables are as defined above for
Formula I.

[0028]In an embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--O--; Y is --NHCO--; A2 is N; A3 is CH optionally substituted
with halo, methyl, methoxy, or trifluoromethyl; and the other variables
are as defined above for Formula I.

[0029]In an embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--O--; Y is --NHCO--; A1 is CH; A2 is N; A3 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0030]In an embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--O--; Y is --NHCO--; A1 is N; A2 is N; A3 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0031]In an embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--O--; Y is --NHCO--; A3 is N; A2 is CH optionally substituted
with halo, methyl, methoxy, or trifluoromethyl; and the other variables
are as defined above for Formula I.

[0032]In an embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--O--; Y is --NHCO--; A1 is CH; A3 is N; A2 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0033]In an embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--O--; Y is --NHCO--; A1 is N; A3 is N; A2 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0034]In another embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--O--; Y is --CONH--; and the other variables are as defined above for
Formula I.

[0035]In another embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--O--; Y is --CONH--; A2 is N; A3 is CH optionally substituted
with halo, methyl, methoxy, or trifluoromethyl; and the other variables
are as defined above for Formula I.

[0036]In another embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--O--; Y is --CONH--; A1 is CH; A2 is N; A3 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0037]In another embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--O--; Y is --CONH--; A1 is N; A2 is N; A3 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0038]In another embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--O--; Y is --CONH--; A3 is N; A2 is CH optionally substituted
with halo, methyl, methoxy, or trifluoromethyl; and the other variables
are as defined above for Formula I.

[0039]In another embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--O--; Y is --CONH--; A1 is CH; A3 is N; A2 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0040]In another embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--O--; Y is --CONH--; A1 is N; A3 is N; A2 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0041]In still another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --O--; Y is --NHSO2--; and the other variables are as
defined above for Formula I.

[0042]In still another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --O--; Y is --NHSO2--; A2 is N; A3 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0043]In still another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --O--; Y is --NHSO2--; A1 is CH; A2 is N;
A3 is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0044]In still another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --O--; Y is --NHSO2--; A1 is N; A2 is N;
A3 is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0045]In still another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --O--; Y is --NHSO2--; A3 is N; A2 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0046]In still another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --O--; Y is --NHSO2--; A1 is CH; A3 is N;
A2 is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0047]In still another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --O--; Y is --NHSO2--; A1 is N; A3 is N;
A2 is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0048]In another embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--O--; Y is --NHCONH--; and the other variables are as defined above for
Formula I.

[0049]In another embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--O--; Y is --NHCONH--; A2 is N; A3 is CH optionally
substituted with halo, methyl, methoxy, or trifluoromethyl; and the other
variables are as defined above for Formula I.

[0050]In another embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--O--; Y is --NHCONH--; A2 is N; A1 is CH; A3 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0051]In another embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--O--; Y is --NHCONH--; A2 is N; A1 is N; A3 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0052]In another embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--O--; Y is --NHCONH--; A3 is N; A2 is CH optionally
substituted with halo, methyl, methoxy, or trifluoromethyl; and the other
variables are as defined above for Formula I.

[0053]In another embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--O--; Y is --NHCONH--; A1 is CH; A3 is N; A2 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0054]In another embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--O--; Y is --NHCONH--; A1 is N; A3 is N; A2 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0055]In yet another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --O--; Y is --NHCH2--; and the other variables are as
defined above for Formula I.

[0056]In yet another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --O--; Y is --NHCH2--; A2 is N; A3 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0057]In yet another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --O--; Y is --NHCH2--; A1 is CH; A2 is N;
A3 is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0058]In yet another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --O--; Y is --NHCH2--; A1 is N; A2 is N;
A3 is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0059]In yet another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --O--; Y is --NHCH2--; A3 is N; A2 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0060]In yet another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --O--; Y is --NHCH2--; A1 is CH; A3 is N;
A2 is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0061]In yet another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --O--; Y is --NHCH2--; A1 is N; A3 is N;
A2 is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0062]In another aspect, the compounds of the present invention are
represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)- and the other variables are as defined above for
Formula I.

[0063]In an embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)-; Y is --NHCO--; and the other variables are as
defined above for Formula I.

[0064]In an embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)-; Y is --NHCO--; A2 is N; A3 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0065]In an embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)-; Y is --NHCO--; A1 is CH; A2 is N; A3
is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0066]In an embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)-; Y is --NHCO--; A1 is N; A2 is N; A3
is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0067]In an embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)-; Y is --NHCO--; A3 is N; A2 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0068]In an embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)-; Y is --NHCO--; A1 is CH; A3 is N; A2
is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0069]In an embodiment of this aspect, the compounds of the present
invention are represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)-; Y is --NHCO--; A1 is N; A3 is N; A2
is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0070]In yet another embodiment, the compounds of the present invention
are represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)-; Y is --CONH--; and the other variables are as
defined above for Formula I.

[0071]In yet another embodiment, the compounds of the present invention
are represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)-; Y is --CONH--; A2 is N; A3 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0072]In yet another embodiment, the compounds of the present invention
are represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)-; Y is --CONH--; A1 is CH; A2 is N; A3
is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0073]In yet another embodiment, the compounds of the present invention
are represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)-; Y is --CONH--; A1 is N; A2 is N; A3
is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0074]In yet another embodiment, the compounds of the present invention
are represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)-; Y is --CONH--; A3 is N; A2 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0075]In yet another embodiment, the compounds of the present invention
are represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)-; Y is --CONH--; A1 is CH; A3 is N; A2
is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0076]In yet another embodiment, the compounds of the present invention
are represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)-; Y is --CONH--; A1 is N; A3 is N; A2
is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0077]In still another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --N(C0-6alkyl)-; Y is --NHSO2--; and the other
variables are as defined above for Formula I.

[0078]In still another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --N(C0-6alkyl)-; Y is --NHSO2--; A2 is N;
A3 is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0079]In still another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --N(C0-6alkyl)-; Y is --NHSO2--; A1 is CH;
A2 is N; A3 is CH optionally substituted with halo, methyl,
methoxy, or trifluoromethyl; and the other variables are as defined above
for Formula I.

[0080]In still another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --N(C0-6alkyl)-; Y is --NHSO2--; A1 is N;
A2 is N; A3 is CH optionally substituted with halo, methyl,
methoxy, or trifluoromethyl; and the other variables are as defined above
for Formula I.

[0081]In still another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --N(C0-6alkyl)-; Y is --NHSO2--; A3 is N;
A2 is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0082]In still another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --N(C0-6alkyl)-; Y is --NHSO2--; A1 is CH;
A3 is N; A2 is CH optionally substituted with halo, methyl,
methoxy, or trifluoromethyl; and the other variables are as defined above
for Formula I.

[0083]In still another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --N(C0-6alkyl)-; Y is --NHSO2--; A1 is N;
A3 is N; A2 is CH optionally substituted with halo, methyl,
methoxy, or trifluoromethyl; and the other variables are as defined above
for Formula I.

[0084]In another embodiment, the compounds of the present invention are
represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)-; Y is --NHCONH--; and the other variables are as
defined above for Formula I.

[0085]In another embodiment, the compounds of the present invention are
represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)-; Y is --NHCONH--; A2 is N; A3 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0086]In another embodiment, the compounds of the present invention are
represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)-; Y is --NHCONH--; A1 is CH; A2 is N;
A3 is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0087]In another embodiment, the compounds of the present invention are
represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)-; Y is --NHCONH--; A1 is N; A2 is N;
A3 is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0088]In another embodiment, the compounds of the present invention are
represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)-; Y is --NHCONH--; A3 is N; A2 is CH
optionally substituted with halo, methyl, methoxy, or trifluoromethyl;
and the other variables are as defined above for Formula I.

[0089]In another embodiment, the compounds of the present invention are
represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)-; Y is --NHCONH--; A1 is CH; A3 is N;
A2 is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0090]In another embodiment, the compounds of the present invention are
represented by Formula I in free or salt form, wherein W is
--N(C0-6alkyl)-; Y is --NHCONH--; A1 is N; A3 is N;
A2 is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0091]In yet another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --N(C0-6alkyl)-; Y is --NHCH2--; and the other
variables are as defined above for Formula I.

[0092]In yet another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --N(C0-6alkyl)-; Y is --NHCH2--; A2 is N;
A3 is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0093]In yet another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --N(C0-6alkyl)-; Y is --NHCH2--; A1 is CH;
A2 is N; A3 is CH optionally substituted with halo, methyl,
methoxy, or trifluoromethyl; and the other variables are as defined above
for Formula I.

[0094]In yet another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --N(C0-6alkyl)-; Y is --NHCH2--; A1 is N;
A2 is N; A3 is CH optionally substituted with halo, methyl,
methoxy, or trifluoromethyl; and the other variables are as defined above
for Formula I.

[0095]In yet another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --N(C0-6alkyl)-; Y is --NHCH2--; A3 is N;
A2 is CH optionally substituted with halo, methyl, methoxy, or
trifluoromethyl; and the other variables are as defined above for Formula
I.

[0096]In yet another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --N(C0-6alkyl)-; Y is --NHCH2--; A1 is CH;
A3 is N; A2 is CH optionally substituted with halo, methyl,
methoxy, or trifluoromethyl; and the other variables are as defined above
for Formula I.

[0097]In yet another embodiment of this aspect, the compounds of the
present invention are represented by Formula I in free or salt form,
wherein W is --N(C0-6alkyl)-; Y is --NHCH2--; A1 is N;
A3 is N; A2 is CH optionally substituted with halo, methyl,
methoxy, or trifluoromethyl; and the other variables are as defined above
for Formula I.

[0098]In another aspect, the present invention comprises any of the
following compounds:

##STR00006## ##STR00007##

[0099]The invention therefore comprises any of the following: [0100]1.1
Compounds of Formula (Q) or Formula (I), wherein W is --O-- or
--N(C0-6alkyl)-; [0101]1.2 Compounds of Formula (Q) or Formula (I)
or 1.1, wherein W is --N(C0-6alkyl)-; [0102]1.3 Compounds of Formula
(Q) or Formula (I) or 1.1 or 1.2, wherein W is --NH--; [0103]1.4
Compounds of Formula (Q) or Formula (I), 1.1-1.3, wherein Y is --NHCO--,
--CONH--, --NHSO2--, --NHCONH--, or --NHCH2--; [0104]1.5
Compounds of Formula (Q) or Formula (I), or any of 1.1-1.4, wherein Y is
--NHSO2--; [0105]1.6 Compounds of Formula (Q) or Formula (I), or any
of 1.1-1.4, wherein Y is --CONH--; [0106]1.7 Compounds of Formula (Q) or
Formula (I), or any of 1.1-1.4, wherein Y is --NHCO--; [0107]1.8
Compounds of Formula (Q) or Formula (I) or any of 1.1-1.7, wherein
A1 is --N--; [0108]1.9 Compounds of Formula (Q) or Formula (I) or
any of 1.1-1.7, wherein A1 is --C(R7)--; [0109]1.10 Compounds
of Formula (Q) or Formula (I) or any of 1.1-1.7 or 1.9, wherein A1
is --C(H)--; [0110]1.11 Compounds of Formula (Q) or Formula (I) or any of
1.1-1.10, wherein A2 is --N--; [0111]1.12 Compounds of Formula (Q)
or Formula (I) or any of 1.1-1.10, wherein A2 is --C-- optionally is
substituted with R8; [0112]1.13 Compounds of Formula (Q) or Formula
(I) or any of 1.1-1.12, wherein A3 is --N--; [0113]1.14 Compounds of
Formula (Q) or Formula (I) or any of 1.1-1.11, wherein A3 is --C--
optionally is substituted with R8; [0114]1.15 Formula 1.14, wherein
R8 is hydrogen, halo, C1-4alkyl (e.g., methyl),
C1-4alkoxyl (e.g., methoxy), or haloC1-4alkyl (e.g.,
trifluoromethyl); [0115]1.16 Formula 1.14 or 1.15, wherein R8 is
hydrogen [0116]1.17 Formula 1.14, wherein R8 is C1-4alkyl
(e.g., methyl); [0117]1.18 Compounds of Formula (Q) or Formula (I) or any
of 1.1-1.17, wherein D is a 5 or 6 membered aryl, hetaryl or hetcyclic
ring having at least one N, S, or O ring atom or a C ring atom forming an
oxo (C═O) moiety; [0118]1.19 Compounds of Formula (Q) or Formula (I)
or any of 1.1-1.18, wherein D is a 5 or 6 membered aryl, hetaryl or
hetcyclic ring having at least one N, S, or O ring atom; [0119]1.20
Compounds of Formula (Q) or Formula (I) or any of 1.1-1.19, wherein D is
aryl; [0120]1.21 Compounds of Formula (Q) or Formula (I) or any of
1.1-1.20, wherein D is phenyl; [0121]1.22 Compounds of Formula (Q) or
Formula (I) or any of 1.1-1.21, wherein R1 is C1-6alkyl, aryl,
or hetaryl; optionally substituted except at the ortho position of the
aryl or hetaryl with 1-6 halo, C1-6alkoxy, C1-6alkyl, or
trifluoromethyl substituents; [0122]1.23 Compounds of Formula (Q) or
Formula (I) or any of 1.1-1.22, wherein R1 is aryl optionally
substituted except at the ortho position of the aryl with 1-6 halo,
C1-6alkoxy, C1-6alkyl, or trifluoromethyl substituents;
[0123]1.24 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.23,
wherein R1 is phenyl optionally substituted except at the ortho
position of the phenyl with 1-6 halo, C1-6alkoxy, C1-6alkyl, or
trifluoromethyl; [0124]1.25 Compounds of Formula (Q) or Formula (I) or
any of 1.1-1.24, wherein R1 is phenyl; [0125]1.26 Compounds of
Formula (Q) or Formula (I) or any of 1.1-1.25, wherein R1 is
p-methoxyphenyl, m-trifluoromethylphenyl or p-methylphenyl; [0126]1.27
Compounds of Formula (Q) or Formula (I) or any of 1.1-1.22, wherein
R1 is hetaryl optionally substituted except at the ortho position of
the hetaryl with 1-6 halo, C1-6alkoxy, C1-6alkyl, or
trifluoromethyl substituents; [0127]1.28 Compounds of Formula (Q) or
Formula (I) or any of 1.1-1.22 or 1.27, wherein R1 is pyridyl;
[0128]1.29 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.22 or
1.27-1.28, wherein R1 is pyrid-3-yl; [0129]1.30 Compounds of Formula
(Q) or Formula (I) or any of 1.1-1.29, wherein R2 is C0-6alkyl,
C3-7cycloalkyl, aryl, hetaryl, aryl(C1-4alkyl)-,
hetcyclyl(C0-4alkyl)-, or
--C0-6alkyl-N(C0-6alkyl)(C0-6alkyl), optionally
substituted with C1-6alkyl; [0130]1.31 Compounds of Formula (Q) or
Formula (I) or any of 1.1-1.30, wherein R2 is
hetcyclyl(C0-4alkyl)- optionally substituted with C1-6alkyl;
[0131]1.32 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.31,
wherein R2 is piperidin-1-yl(C0-4alkyl)-,
piperidin-4-yl(C0-4alkyl)-, piperazin-1-yl(C0-4alkyl) or
piperazin-4-yl(C0-4alkyl), optionally substituted with
C1-6alkyl; [0132]1.33 Compounds of Formula (Q) or Formula (I) or any
of 1.1-1.32, wherein R2 is piperidin-1-ylmethyl-,
4-methylpiperidin-1-ylmethyl, N-methylpiperidin-4-ylmethyl-,
piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl or
4-ethylpiperazin-1-ylmethyl; [0133]1.34 Compounds of Formula (Q) or
Formula (I) or any of 1.1-1.33, wherein R3, R4, R5,
R6, R7 and R8 are independently selected from hydrogen,
halo, C1-4alkyl (e.g., methyl), C1-4alkoxyl (e.g., methoxy),
and haloC1-4alkyl (e.g., trifluoromethyl); [0134]1.35 Compounds of
Formula (Q) or Formula (I) or any of 1.1-1.34, wherein R3 is
hydrogen; [0135]1.36 Compounds of Formula (Q) or Formula (I) or any of
1.1-1.35, wherein R4 is hydrogen; [0136]1.37 Compounds of Formula
(Q) or Formula (I) or any of 1.1-1.36, wherein R4 is C1-4alkyl
(e.g., methyl); [0137]1.38 Compounds of Formula (Q) or Formula (I) or any
of 1.1-1.35 or 1.37, wherein R4 is methyl; [0138]1.39 Compounds of
Formula (Q) or Formula (I) or any of 1.1-1.38, wherein, the present
invention comprises any of the following compounds:

##STR00008## ##STR00009##

[0139]in free or salt form.

[0140]The term "alkyl" includes both straight and branched chain alkyl
groups. References to individual alkyl groups such as "propyl" are
specific for the straight chain version only and references to individual
branched chain alkyl groups such as `isopropyl` are specific for the
branched chain version only. For example, "C1-6alkyl" includes
C1-4alkyl, C1-3alkyl, propyl, isopropyl and t-butyl. A similar
convention applies to other radicals, for example "phenylC1-6alkyl"
includes phenylC1-4alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.
"C0alkyl" refers to a hydrogen terminus when the C0alkyl is
terminal and refers to a direct bond when the "C0alkyl" is bridging
(linking). The term "C0-6alkyl", for example, refers to adding
"C0alkyl" to the scope of the "C1-6alkyl" definition. Thus, it
is understood that substituents allowed for "C1-6alkyl" would
accordingly be allowed for the "C1-6alkyl" within the scope of
"C0-6alkyl".

[0141]The term "halo" refers to fluoro, chloro, bromo and iodo.

[0142]Where optional substituents are chosen from, for example, "1-5
independent" substituents from a list of substituents, it is to be
understood that this definition includes all substituents being chosen
from one of the specified groups or the substituents being chosen from
two or more of the specified groups in the list. Where a substituent is
recited using the molecule (parent) name, it is understood that the
substituent is the radical of such molecular parent.

[0143]An "aryl" is well understood by one in the art and includes phenyl
and naphthyl.

[0147]Examples of "--(C0-6alkyl)-N(C0-6alkyl)(C0-6alkyl)"
include methylamino, ethylamino, di-N-methylamino, di-(N-ethyl)amino, and
N-ethyl-N-methylamino.

[0148]A suitable salt of a compound of the invention is, for example, an
acid-addition salt of a compound of the invention which is sufficiently
basic, for example, an acid-addition salt with, for example, an inorganic
or organic acid, for example hydrochloric, hydrobromic, sulphuric,
phosphoric, trifluoroacetic, citric or maleic acid. In addition a
suitable salt of a compound of the invention which is sufficiently acidic
is an alkali metal salt, for example a sodium or potassium salt, an
alkaline earth metal salt, for example a calcium or magnesium salt, an
ammonium salt or a salt with an organic base which affords a
physiologically-acceptable cation, for example a salt with methylamine,
dimethylamine, trimethylamine, piperidine, morpholine or
tris-(2-hydroxyethyl)amine. The Compounds of the Invention, e.g.,
compounds of formula (Q) or formula (I), e.g., any of 1.1-1.39, are
intended for use as pharmaceuticals, therefore pharmaceutically
acceptable salts are preferred. Salts which are unsuitable for
pharmaceutical uses may nevertheless be useful, for example, for the
isolation or purification of free Compounds of the Invention.
Consequently, the present invention encompasses novel Compounds of
Formula (Q) and formula (I), in free or salt form, including salts that
are suitable as well as salts which are unsuitable for pharmaceutical
use.

[0149]According to a further aspect of the invention there is provided a
pharmaceutical composition which comprises a compound of the formula (I),
or a pharmaceutically acceptable salt thereof, as defined hereinbefore,
in association with a pharmaceutically-acceptable diluent or carrier. In
another aspect of the invention, there is provided a pharmaceutical
composition which comprises a compound of formula (Q) or formula (I),
e.g., any of 1.1-1.39, in free or pharmaceutically acceptable salt form,
in association with a pharmaceutically acceptable diluent or carrier.

[0150]The composition may be in a form suitable for oral administration,
for example as a tablet or capsule, for parenteral injection (including
intravenous, subcutaneous, intramuscular, intravascular or infusion) as a
sterile solution, suspension or emulsion, for topical administration as
an ointment or cream or for rectal administration as a suppository.

[0151]In general the above compositions may be prepared in a conventional
manner using conventional excipients.

[0152]The compound of formula (I) will normally be administered to a
warm-blooded animal at a unit dose within the range 1-1000 mg/kg, and
this normally provides a therapeutically-effective dose. Preferably a
daily dose in the range of 10-100 mg/kg is employed. Similarly, the
compound of formula (Q) or any of 1.1-1.39 may also be administered to a
warm-blooded animal at a unit dose within the range of 1-1000 mg/kg,
preferably a daily dose in the range of 10-100 mg/kg. However the daily
dose will necessarily be varied depending upon the host treated, the
particular route of administration, and the severity of the illness being
treated. Accordingly the optimum dosage may be determined by the
practitioner who is treating any particular patient.

[0153]According to a further aspect of the present invention there is
provided a compound of the formula (I), or a pharmaceutically acceptable
salt thereof, as defined hereinbefore for use in a method of treatment of
the human or animal body by therapy. The invention also provides a
compound of formula (Q), or any of 1.1-1.39, in free or pharmaceutically
acceptable salt form, for use in a method of treatment of the human or
animal body by therapy.

[0154]We have found that the compounds defined in the present invention,
or a pharmaceutically acceptable salt thereof, can penetrate the
blood-brain barrier and inhibit the formation and accumulation of
beta-amyloid. Accordingly the compounds of the present invention are
useful in the treatment of neurodegenerative diseases, particularly
Alzheimer's disease. Therefore, the invention provides a compound of
formula (Q) or formula (I), e.g., any of 1.1-1.39, in free or
pharmaceutically acceptable salt form, which penetrates the blood-brain
barrier and inhibit the formation and accumulation of beta-amyloid. The
invention also provides a compound of formula (Q) or formula (I), e.g.,
any of 1.1-1.39, in free or pharmaceutically acceptable salt form, useful
for the treatment of neurodegenerative diseases, particularly Alzheimer's
disease.

[0155]We have found that the compounds defined in the present invention,
or a pharmaceutically acceptable salt thereof, can inhibit certain
kinases. Accordingly the compounds of the present invention are useful in
the treatment of cancers of the central nervous system. Therefore, the
invention provides a compound of formula (q) or formula (I), e.g., any of
1.1-1.39, in free or pharmaceutically acceptable salt form, useful in the
treatment of cancers of the central nervous system.

[0156]Thus according to this aspect of the invention there is provided a
compound of the formula (I), or a pharmaceutically acceptable salt
thereof, as defined hereinbefore for use as a medicament.

[0157]According to a further aspect of the invention there is provided the
use of a compound of the formula (I), or a pharmaceutically acceptable
salt thereof, as defined hereinbefore in the manufacture of a medicament
for use in the inhibition of the formation and accumulation of
beta-amyloid in a warm-blooded animal such as man. Use of a compound of
the formula (Q) or formula (I), e.g., any of 1.1-1.39, in free or
pharmaceutically acceptable salt form, as defined hereinbefore in the
manufacture of a medicament for use in the inhibition of the formation
and accumulation of beta-amyloid in a warm-blooded animal such as man.

[0158]According to an aspect of the invention there is provided the use of
a compound of the formula (I), or a pharmaceutically acceptable salt
thereof, as defined hereinbefore in the manufacture of a medicament for
use in the production of an inhibition of certain kinases across the
blood-brain barrier in a warm-blooded animal such as man. In another
aspect, the invention also provides use of a compound for formula (Q) or
formula (I), e.g., any of 1.1-1.39, in free or pharmaceutically
acceptable salt form, in the manufacture of a medicament for use in the
production of an inhibition of certain kinases across the blood-brain
barrier in a warm-blooded animal such as a man.

[0159]According to a further feature of the invention, there is provided
the use of a compound of the formula (I), in free or salt form, as
defined herein before in the manufacture of a medicament for use in the
treatment of cancers of the nervous system and the brain. In still
another feature of the invention, there is provided use of a compound of
the formula (Q) or formula (I), e.g., any of 1.1-1.39, in free or
pharmaceutically acceptable salt form, as defined herein before in the
manufacture of a medicament for use in the treatment of cancers of the
nervous system and the brain.

[0160]According to a further feature of this aspect of the invention there
is provided a method for producing an inhibitory effect against the
accumulation of abnormal protein aggregates in a warm-blooded animal,
such as man, in need of such treatment which comprises administering to
said animal an effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt thereof. In still another feature of
this aspect of the invention, there is provided a method for producing an
inhibitory effect against the accumulation of abnormal protein aggregates
in a warm-blooded animal, such as man, in need of such treatment which
comprises administering to said animal an effective amount of a compound
of formula (Q) or formula (I), e.g., any of 1.1-1.39, in free or
pharmaceutically acceptable salt form.

[0161]Furthermore, the compounds of this invention are useful in the
treatment, control and management of diseases characterized by
accumulation of abnormal protein aggregates, especially in the brain--for
example, diseases such as Alzheimer's disease, progressive supranuclear
palsy, Down Syndrome, memory and cognitive disorders, dementia, amyloid
neuropathies, brain inflammation, nerve and brain trauma, vascular
amyloidosis, cerebral hemorrhage with amyloidosis, Parkinson's disease,
Huntington's disease, prion disease and/or vascular, neurological, and/or
neurodegenerative disorders related to the abnormal expression or
accumulation of tau or amyloid proteins such as Aβ. Such abnormal
protein aggregates include, for example, i) amyloid plaques and
neurofibrillary tangles, and ii) precipitates of tau or amyloid proteins
such as Aβ.

[0163]Additionally, the present invention provides methods of treatment of
hyperproliferative diseases, especially cancers of the brain or central
nervous system, including astrocytoma, medulloblastoma, oligdendroglioma,
glioblastoma, glioma, ependymoma, meningioma, sarcoma, germ cell tumor,
pinealoma, craniopharyngioma, and pituitary adenoma. The present
invention also provides methods of treatment of hyperproliferative
diseases as described herein comprising administering to a patient in
need thereof a compound of formula (Q) or formula (I), e.g., any of
1.1-1.39, in free or pharmaceutically acceptable salt form.

[0164]The present invention also provides methods of treatment of disease
characterized by dysfunctional expression or activity of kinases such as
the c-Ab1, BCR-Ab1, ARG, c-Src, c-Kit, FAK, Trk, EGFR, VEGFR, Tie-2,
c-Met, FGFR-1, Flt-1, Her-2, c-Raf, PDGFR, PDGFR-beta, MAPK, PKA, PKC,
PKCα, PKCδ, CDK5, GSK-3, or JNK, especially over-expression
or over-activity of kinases in CNS cells, comprising the administration
of an effective amount of a compound or composition of the present
invention in free or salt form to a human or animal patient in need
thereof. The compound or composition of the present invention includes
compounds of formula (Q) or formula (I), e.g., any of 1.1-1.39, in free
or pharmaceutically acceptable salt form.

[0165]In a further aspect of the invention there is provided a
pharmaceutical composition which comprises a compound of the formula (I),
or a pharmaceutically acceptable salt thereof, as defined herein before
in association with a pharmaceutically-acceptable diluent or carrier for
use in the treatment, control and management of diseases characterized by
accumulation of abnormal protein aggregates, especially in the brain,
such as Alzheimer's disease, progressive supranuclear palsy, Down
Syndrome, memory and cognitive disorders, dementia, amyloid neuropathies,
brain inflammation, nerve and brain trauma, vascular amyloidosis,
cerebral hemorrhage with amyloidosis, Parkinson's disease, Huntington's
disease, prion disease and/or vascular, neurological, and/or
neurodegenerative disorders related to the abnormal expression or
accumulation of tau or amyloid proteins such as Aβ. In another
embodiment, the invention provides a pharmaceutical composition which
comprises a compound of the formula (Q) or formula (I), e.g., any of
1.1-1.39, in free or pharmaceutically acceptable salt form, as defined
herein before in association with a pharmaceutically-acceptable diluent
or carrier for use in the treatment, control and management of diseases
characterized by accumulation of abnormal protein aggregates, especially
in the brain, such as Alzheimer's disease, progressive supranuclear
palsy, Down Syndrome, memory and cognitive disorders, dementia, amyloid
neuropathies, brain inflammation, nerve and brain trauma, vascular
amyloidosis, cerebral hemorrhage with amyloidosis, Parkinson's disease,
Huntington's disease, prion disease and/or vascular, neurological, and/or
neurodegenerative disorders related to the abnormal expression or
accumulation of tau or amyloid proteins such as Aβ. Such abnormal
protein aggregates include, for example, i) amyloid plaques and
neurofibrillary tangles, and ii) precipitates of tau or amyloid proteins
such as Aβ.

[0166]In a further aspect of the invention there is provided a
pharmaceutical composition which comprises a compound of the formula (I),
or a pharmaceutically acceptable salt thereof, as defined herein before
in association with a pharmaceutically-acceptable diluent or carrier for
use in the treatment of Alzheimer's disease, progressive supranuclear
palsy, Down Syndrome, memory and cognitive disorders, dementia, amyloid
neuropathies, brain inflammation, nerve and brain trauma, vascular
amyloidosis, cerebral hemorrhage with amyloeiosis, Parkinson's disease,
Huntington's disease, prion disease and/or vascular, neurological, and/or
neurodegenerative disorders related to the abnormal expression or
accumulation of tau or amyloid proteins such as Aβ. In still another
aspect of the invention, there is provided a pharmaceutical composition
which comprises a compound of the formula (Q) or formula (I), any of
1.1-1.39, in free or pharmaceutically acceptable salt form, as defined
herein before in association with a pharmaceutically acceptable diluent
or carrier for use in the treatment of Alzheimer's disease, progressive
supranuclear palsy, Down Syndrome, memory and cognitive disorders,
dementia, amyloid neuropathies, brain inflammation, nerve and brain
trauma, vascular amyloidosis, cerebral hemorrhage with amyloeiosis,
Parkinson's disease, Huntington's disease, prion disease and/or vascular,
neurological, and/or neurodegenerative disorders related to the abnormal
expression or accumulation of tau or amyloid proteins such as Aβ.

[0168]Such conjoint treatment may be achieved by way of the simultaneous,
sequential or separate dosing of the individual components of the
treatment. Such combination products employ the compounds of this
invention within the dosage range described hereinbefore and the other
pharmaceutically-active agent within its approved dosage range.

[0169]In addition to their use in therapeutic medicine, the compounds of
formula (I) and their pharmaceutically acceptable salts are also useful
as pharmacological tools in the development and standardisation of in
vitro and in vivo test systems for the evaluation of the effects of
inhibitors of accumulation of abnormal protein aggregates, especially in
the brain, as part of the search for new therapeutic agents.

[0170]In a further aspect of the invention there is provided a
pharmaceutical composition which comprises a compound of the formula (I),
or a pharmaceutically acceptable salt thereof, as defined herein before
in association with a pharmaceutically-acceptable diluent or carrier for
use in the of treatment of hyperproliferative diseases, especially
cancers of the brain or central nervous system, including astrocytoma,
medulloblastoma, oligdendroglioma, glioblastoma, glioma, ependymoma,
meningioma, sarcoma, germ cell tumor, pinealoma, craniopharyngioma, and
pituitary adenoma. In another aspect, the invention also provides a
pharmaceutical composition which comprises a compound of formula (Q) or
(I), e.g., any of 1.1-1.39, in free or pharmaceutically acceptable salt
thereof, as defined herein before in association with a
pharmaceutically-acceptable diluent or carrier for use in the of
treatment of hyperproliferative diseases, especially cancers of the brain
or central nervous system, including astrocytoma, medulloblastoma,
oligdendroglioma, glioblastoma, glioma, ependymoma, meningioma, sarcoma,
germ cell tumor, pinealoma, craniopharyngioma, and pituitary adenoma.

[0171]In a further aspect of the invention there is provided a
pharmaceutical composition which comprises a compound of the formula (I),
or a pharmaceutically acceptable salt thereof, as defined herein before
in association with a pharmaceutically-acceptable diluent or carrier for
use in the treatment of astrocytoma, medulloblastoma, oligdendroglioma,
glioblastoma, glioma, ependymoma, meningioma, sarcoma, germ cell tumor,
pinealoma, craniopharyngioma, and pituitary adenoma. In still another
aspect, the invention provides a compound of the formula (Q) or formula
(I), e.g., any of 1.1-1.39, in free or pharmaceutically acceptable salt
form, as defined herein before in association with a
pharmaceutically-acceptable diluent or carrier for use in the treatment
of astrocytoma, medulloblastoma, oligdendroglioma, glioblastoma, glioma,
ependymoma, meningioma, sarcoma, germ cell tumor, pinealoma,
craniopharyngioma, and pituitary adenoma.

[0172]The treatment methods include administering the compounds of the
present invention, e.g., compound of formula (Q) or formula (I), e.g.,
any of 1.1-1.39, in free or salt form, together with other therapeutic
compounds to treat hyperproliferative diseases, especially cancers of the
brain or central nervous system, including astrocytoma, medulloblastoma,
oligdendroglioma, glioblastoma, glioma, ependymoma, meningioma, sarcoma,
germ cell tumor, pinealoma, craniopharyngioma, and pituitary adenoma.

[0173]Such conjoint treatment may be achieved by way of the simultaneous,
sequential or separate dosing of the individual components of the
treatment. Such combination products employ the compounds of this
invention within the dosage range described hereinbefore and the other
pharmaceutically-active agent within its approved dosage range.

[0174]In addition to their use in therapeutic medicine, the compounds of
formula (I) and their pharmaceutically acceptable salts are also useful
as pharmacological tools in the development and standardisation of in
vitro and in vivo test systems for the evaluation of the effects of
dysfunctional expression or activity of kinases such as the c-Ab1,
BCR-Ab1, ARG, c-Src, c-Kit, FAK, Trk, EGFR, VEGFR, Tie-2, c-Met, FGFR-1,
Flt-1, Her-2, c-Raf, PDGFR, PDGFR-beta, MAPK, PKA, PKC, PKCα,
PKCδ, CDK5, GSK-3, or JNK, especially over-expression or
over-activity of kinases in CNS cells, as part of the search for new
therapeutic agents. Similarly, the compounds of formula (Q), e.g., any of
1.1-1.39, in free or pharmaceutically acceptable salt forms, are also
useful as pharmacological tools in the development and standardisation of
in vitro and in vivo test systems for the evaluation of the effects of
dysfunctional expression or activity of kinases as hereinbefore
described.

[0175]In the above other pharmaceutical composition, process, method, use
and medicament manufacture features, the alternative and preferred
embodiments of the compounds of the invention described herein also
apply.

EXAMPLES

[0176]The invention will now be illustrated by the following non limiting
examples in which, unless stated otherwise:

(i) temperatures are given in degrees Celsius (° C.); operations
were carried out at room or ambient temperature ("rt") were at a
temperature in the range of 18-25° C.;(ii) organic solutions were
dried over anhydrous sodium sulphate; evaporation of solvent is carried
out using a rotary evaporator under reduced pressure (600-4000 Pascals;
4.5-30 mmHg) with a bath temperature of up to 60° C.;(iii) in
general, the course of reactions is followed by TLC and reaction times
are given for illustration only;(iv) final products had satisfactory
proton nuclear magnetic resonance (NMR) spectra and/or mass spectral
data;(v) yields are given for illustration only and are not necessarily
those which can be obtained by diligent process development; preparations
were repeated if more material is required;(vii) when given, NMR data is
in the form of delta values for major diagnostic protons, given in parts
per million (ppm) relative to tetramethylsilane (TMS) as an internal
standard, determined at 400 MHz using perdeuterio dimethyl sulphoxide
(DMSO-d6) as solvent unless otherwise indicated;(vii) chemical
symbols have their usual meanings; SI units and symbols are used;(viii)
solvent ratios are given in volume:volume (v/v) terms; and(ix) mass
spectra were run with an electron energy of 70 electron volts in the
chemical ionization (CI) mode using a direct exposure probe; where
indicated ionization is effected by electron impact (EI), fast atom
bombardment (FAB) or electrospray (ESP); values for m/z are given;
generally, only ions which indicate the parent mass are reported; and
unless otherwise stated, the mass ion quoted is [MH].sup.+;(x) where a
synthesis is described as being analogous to that described in a previous
example the amounts used are the millimolar ratio equivalents to those
used in the previous example;(xi) the following abbreviations have been
used:

[0203]DIEA (473 μL, 2.72 mmol) was added into a solution of
5-bromonicotinic acid (178 mg, 0.881 mmol),
4-((4-methylpiperidin-1-yl)methyl)benzenamine (150 mg, 0.734 mmol), BOP
(487 mg, 1.10 mmol) in DMF (3 mL). The reaction mixture is stirred at rt
under argon atmosphere overnight. The reaction mixture was diluted with
80 mL of AcOEt, and then washed with 1N NaOH aqueous solution three
times. Organic phase was dried with anhydrous Na2SO4, and then
evaporated to remove organic solvents. The obtained residue was further
dried under high vacuum overnight to give crude product, which was used
directly for the next step synthesis without further purification. MS
(ESI.sup.+) m/z 388.1 [M+H].sup.+.

Mouse Brain/Plasma Distribution Assay for the Evaluation of Tissue Levels
of Test Compounds

[0214]Compounds are administered sub-cutaneously to C57bl/6 black mice as
a single injection of 1 mg using a 10 mM DMSO solution. After 2 or 4
hours, the mice are sacrificed. Trunk blood is collected into tubes with
potassium-EDTA as anticoagulant and centrifuged at 5000×g for 10
min. The upper plasma phase is decanted from cellular components. Whole
brain is sonicated with 20 mM Tris-HCl, 135 mM NaCl, pH 7.4 buffer,
giving at 200 mg/mL (w/v) homogenate. Brain homogenate or plasma is
extracted with 2 volumes of acetonitrile and clarified by centrifugation
at 15,000×g for 20 min. Extracts are separated by HPLC using a
Waters Alliance 2695 separations module with a Sunfire® C18 column
(3.5 micron, 2.1×50 mm) and a gradient of methanol over 15 min in a
mobile phase of 0.1% formic acid. The separation is monitored by a
Micromass Quattro Micro triple-quadrupole mass-spectrometric detector.
Compound standardization is performed by methods analogous to those
previously reported, e.g., by Zhao, M., et al. (2005) J Chromatogr B
Analyt Technol Biomed Life Sci 819, 73-80; and Appels, N. M et al. (2005)
Rapid Commun Mass Spectrom 19, 2187-2192.

Brain concentration=measured-2% of plasma

B/P ratio=brain concentration/plasma concentration

[0215]Exemplified Compounds of the Invention have a B/P ratio in this
assay at four hours post-administration of greater than 0.6, while having
a brain concentration of greater than 0.3 μM at four hours post
administration compared to the brain concentration of imatinib at four
hours post-administration of less than 0.1 μM, demonstrating a
substantially higher level of penetration and accumulation in the brain
for the Compounds of the Invention.